Patients on hemodialysis have a general immunodeficiency involving both innate and adaptive responses. As the mechanisms contributing to this defect are uncertain, we sought to study the effects of uremia on circulating dendritic cells (DC) in hemodialysis patients. Immunomagnetic beads were used to isolate myeloid and plasmacytoid DCs from healthy donors. Immune-related functions were determined in these cells cultured in either a complete media containing ABO-compatible serum or media containing sera from uremic patients. The myeloid cells were analyzed for costimulatory molecule expression and allo-stimulatory capability following lipopolysaccharide stimulation. The production of interferon-alpha following herpes-simplex virus stimulation by the plasmacytoid cells was also measured. Myeloid DCs incubated with uremic sera demonstrated impaired maturation and decreased allo-stimulatory capacity. Similarly, herpes virus-stimulated plasmacytoid DCs incubated with uremic sera produced significantly less interferon-alpha compared with cells incubated in the complete media. Both small and large molecule uremic toxins inhibited DC functions in vitro. Use of more efficient dialysis to improve small molecule clearance reversed the inhibition of uremic sera on myeloid but not plasmacytoid DC function. We have shown that the immunodeficiency of hemodialysis patients is due to dialyzable uremic toxins.